Exendin-4 Upregulates Adiponectin Level in Adipocytes via Sirt1/Foxo-1 Signaling Pathway

Abstract

Glucagon-like peptide-1 (GLP-1) receptor plays an essential role in regulating glucose metabolism. GLP-1 receptor agonists have been widely used for treating diabetes and other insulin resistance-related diseases. However, mechanisms underlying the anti-diabetic effects of GLP-1 receptor agonists remain largely unknown. In this study, we investigated the effects of GLP-1 agonist exendin-4 on the expression of adiponectin, an insulin sensitizing hormone. We found that exendin-4 increased the expression and secretion of adiponectin both in vitro and in vivo. Our data showed that exendin-4 upregulated adiponectin expression at both mRNA and protein levels in adipocytes and adipose tissues. The effects of exendin-4 on adiponectin expression were dependent on the GLP-1 receptor. We further demonstrated important roles of Sirt1 and transcriptional factor Foxo-1 in mediating the function of exendin-4 in regulating adiponectin expression. Suppression of Sirt1 or Foxo-1 expression significantly impaired exendin-4-induced adiponectin expression. Consistently, exendin-4 up-regulated Sirt1 and Foxo-1 expression in vivo. Our work is the first study demonstrating the role of Sirt1/Foxo-1 in regulating the regulatory function of a GLP-1 receptor agonist in adiponectin expression both in vitro and in vivo. The results provide important information for the mechanism underlying the function of GLP-1R on improving insulin resistance and related diseases.

Insulin deficiency, but not resistance, exaggerates cognitive deficits in transgenic mice expressing human amyloid and tau proteins. Reversal by Exendin‐4 treatment

“…Several studies have shown that Ex4 induced increased adiponectin levels, directly promotes adiponectin secretion in adipocytes and improves insulin sensitivity (Kim Chung et al, 2009;Li et al, 2008;Pastel et al, 2016;Wang et al, 2017). Moreover, improving adiponectin levels with Ex4 treatment correlated with improved learning ability, which is consistent with studies showing a role of adiponectin in cognitive impairments (Kim et al, 2017;Ng et al, 2016;Wang, Jo, & Song, 2019;Zhang et al, 2017).…”

Preventive Effects of Dulaglutide on Disuse Muscle Atrophy Through Inhibition of Inflammation and Apoptosis by Induction of Hsp72 Expression

“…Dulaglutide significantly upregulated the expression of Hsp72 protein in both GA and soleus muscles. As SIRT1 is an upstream target of Hsp72 (Wang et al, 2017) and the induction of SIRT1 expression in the skeletal muscle is related to the activation of AMPK molecule (Lin and Huang, 2016), we hypothesized that the dulaglutide-mediated increase in Hsp72 expression level in the skeletal muscle may be mediated by AMPK activation. The results observed with AMPK inhibitor treatment show that the increase in Hsp72 protein expression after exposure to dulaglutide or Ex-4, GLP-1 receptor agonist, in C2C12 myotubes was regulated by AMPK ( Figures 6F, H).…”

“…Dulaglutide also increased Hsp72 expression in the GA muscle of the non-immobilized control mice ( Figures 6A, B). Hsp72 expression is regulated by sirtuin 1 (SIRT1) (Wang et al, 2017), and GLP-1 receptor agonist could activate SIRT-1 through the induction of AMPK signaling (Lin and Huang, 2016). Therefore, we investigated the effect of dulaglutide or Ex-4 on Hsp72 and p-AMPK expression in C2C12 myotubes in vitro.…”

Fat fibrosis: friend or foe?

“…Several other ECM components, such as secreted protein acidic and rich in cysteine (54,55), biglycan (56), heparan sulfate proteoglycans (57,58), aggrecan (59), entactin (60), laminin (60)(61)(62), and extendin-4 (63,64), also have described roles in adipogenesis. In this Review, we will focus mainly on the involvement of collagens and collagen-cleaving enzymes in obesity-associated metabolic dysfunction.…”